| Literature DB >> 29510987 |
Catherine S Grasso1,2, Marios Giannakis3,4, Daniel K Wells2, Tsuyoshi Hamada5, Xinmeng Jasmine Mu3,4, Michael Quist6,7, Jonathan A Nowak8, Reiko Nishihara5,8,9,10,11, Zhi Rong Qian5, Kentaro Inamura3, Teppei Morikawa3, Katsuhiko Nosho3, Gabriel Abril-Rodriguez6,2, Charles Connolly7, Helena Escuin-Ordinas6,2, Milan S Geybels7, William M Grady12,13, Li Hsu7, Siwen Hu-Lieskovan6,2, Jeroen R Huyghe7, Yeon Joo Kim6,2, Paige Krystofinski6,2, Mark D M Leiserson14, Dennis J Montoya15, Brian B Nadel15, Matteo Pellegrini15, Colin C Pritchard16, Cristina Puig-Saus6,2, Elleanor H Quist6,2, Ben J Raphael14, Stephen J Salipante16, Daniel Sanghoon Shin6,2, Eve Shinbrot17, Brian Shirts16, Sachet Shukla3,4,18, Janet L Stanford7,19, Wei Sun7, Jennifer Tsoi20, Alexander Upfill-Brown6,2, David A Wheeler17, Catherine J Wu3,4, Ming Yu12, Syed H Zaidi21, Jesse M Zaretsky6,2, Stacey B Gabriel4, Eric S Lander4, Levi A Garraway3,4, Thomas J Hudson21,22, Charles S Fuchs23,24,25,26, Antoni Ribas6,2, Shuji Ogino4,5,8,11, Ulrike Peters7,19.
Abstract
To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730-49. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663. ©2018 American Association for Cancer Research.Entities:
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Year: 2018 PMID： 29510987 PMCID： PMC5984687 DOI： 10.1158/2159-8290.CD-17-1327
Source DB: PubMed Journal: Cancer Discov ISSN： 2159-8274 Impact factor: 39.397